scholarly journals An integrative, translational approach to understanding rare and orphan genetically based diseases

2013 ◽  
Vol 3 (2) ◽  
pp. 20120055 ◽  
Author(s):  
Robert Hoehndorf ◽  
Paul N. Schofield ◽  
Georgios V. Gkoutos
Keyword(s):  
Animal Model ◽  
Candidate Genes ◽  
Molecular Basis ◽  
Genetic Diseases ◽  
Clinical Signs ◽  
Mendelian Inheritance ◽  
Disease Phenotypes ◽  
Guilt By Association ◽  
Translational Approach ◽  
Omim Database

PhenomeNet is an approach for integrating phenotypes across species and identifying candidate genes for genetic diseases based on the similarity between a disease and animal model phenotypes. In contrast to ‘guilt-by-association’ approaches, PhenomeNet relies exclusively on the comparison of phenotypes to suggest candidate genes, and can, therefore, be applied to study the molecular basis of rare and orphan diseases for which the molecular basis is unknown. In addition to disease phenotypes from the Online Mendelian Inheritance in Man (OMIM) database, we have now integrated the clinical signs from Orphanet into PhenomeNet. We demonstrate that our approach can efficiently identify known candidate genes for genetic diseases in Orphanet and OMIM. Furthermore, we find evidence that mutations in the HIP1 gene might cause Bassoe syndrome, a rare disorder with unknown genetic aetiology. Our results demonstrate that integration and computational analysis of human disease and animal model phenotypes using PhenomeNet has the potential to reveal novel insights into the pathobiology underlying genetic diseases.

Genetics in Ophthalmology

2020 ◽  
pp. 44-45
Author(s):  
А.Ю. Рудник ◽  
М.А. Федяков ◽  
О.С. Глотов
Keyword(s):  
Genetic Basis ◽  
Genetic Diseases ◽  
Mendelian Inheritance ◽  
Diagnostic Screening ◽  
Online Mendelian Inheritance ◽  
Clinical Diagnostic ◽  
Omim Database

На сегодняшний день в базе данных Online Mendelian Inheritance in Man (OMIM) описано более 6613 заболеваний и фенотипов, 4241 имеют доказанную генетическую основу, не менее 45% вкючают офтальмологические проявления. В статье приведен ряд клинический примеров пациентов с офтальмологическими симптомами различных генетических заболеваний (алкаптонурия, болезнь Штаргардта, синдром микроцефалии с или без хориоретинопатии; астроцитарная гамартома) с целью демонстрации эффективного клинико-диагностического скрининга генетической патологии у пациентов. So far, the Online Mendelian Inheritance in Man (OMIM) database describes more than 6613 diseases and phenotypes, 4241 have a proven genetic basis, 45% of which are combined with ophthalmological manifestations. The article provides a number of clinical examples of patients with ophthalmological manifestations of various genetic diseases (alcaptonuria, Stadgart ‘s disease, microcephaly syndrome with or without choriretinopathy; Astrocytic gamartoma) to demonstrate effective clinical-diagnostic screening of genetic pathology in patients.

scholarly journals Inflammatory responses of C57BL/6NKorl mice to dextran sulfate sodium-induced colitis: comparison between three C57BL/6 N sub-strains

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Sou Hyun Kim ◽  
Doyoung Kwon ◽  
Seung Won Son ◽  
Tae Bin Jeong ◽  
Seunghyun Lee ◽  
...  
Keyword(s):  
Animal Model ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Inflammatory Responses ◽  
Inbred Mouse ◽  
Clinical Signs ◽  
Safety Evaluation ◽  
Inbred Mouse Strain ◽  
Drug Safety Evaluation ◽  
Factor Α

Abstract Background Inflammatory bowel disease (IBD), including both Crohn’s disease and ulcerative colitis, are chronic human diseases that are challenging to cure and are often unable to be resolved. The inbred mouse strain C57BL/6 N has been used in investigations of IBD as an experimental animal model. The purpose of the current study was to compare the inflammatory responsiveness of C57BL/6NKorl mice, a sub-strain recently established by the National Institute of Food and Drug Safety Evaluation (NIFDS), with those of C57BL/6 N mice from two different sources using a dextran sulfate sodium (DSS)-induced colitis model. Results Male mice (8 weeks old) were administered DSS (0, 1, 2, or 3%) in drinking water for 7 days. DSS significantly decreased body weight and colon length and increased the colon weight-to-length ratio. Moreover, severe colitis-related clinical signs including diarrhea and rectal bleeding were observed beginning on day 4 in mice administered DSS at a concentration of 3%. DSS led to edema, epithelial layer disruption, inflammatory cell infiltration, and cytokine induction (tumor necrosis factor-α, interleukin-6, and interleukin-1β) in the colon tissues. However, no significant differences in DSS-promoted abnormal symptoms or their severity were found between the three sub-strains. Conclusions These results indicate that C57BL/6NKorl mice responded to DSS-induced colitis similar to the generally used C57BL6/N mice, thus this newly developed mouse sub-strain provides a useful animal model of IBD.

Determination of the L-ascorbic acid requirements in Wistar osteogenic disorder Shionogi rats for prolonged carcinogenesis experiments

1996 ◽  
Vol 30 (4) ◽  
pp. 337-346 ◽  
Author(s):  
S. W. Y. Chan ◽  
P. C. Reade
Keyword(s):  
Animal Model ◽  
Ascorbic Acid ◽  
Drinking Water ◽  
Normal Level ◽  
Physical Condition ◽  
Wistar Rats ◽  
Clinical Signs ◽  
Supplement Group ◽  
Palatal Mucosa

Wistar Shionogi rats of the ( od/od) substrain with the osteogenic disorder are unable to synthesize L-ascorbic acid ( L-AA) and appear to be an appropriate animal model for studying the effect of L-AA in carcinogenesis. To determine the minimal L-AA requirements of these animals for prolonged survival in a satisfactory physical condition during experimentation, four concentrations of L-AA (0.33 g/l, 0.67 g/l, 1.67 g/l and 3.33 g/l) were administered via drinking water to four groups of animals ( n=2). Their water intake per cage was recorded three times weekly and the plasma L-AA levels were determined at the start, after 2, 4, 8 and 12 weeks and at the termination of the experiment. To simulate the procedures to be undertaken in oral mucosal carcinogenesis experiments, the animals were gently restrained and a designated amount of sterile NaCl was applied to the palatal mucosa three times a week for 26 weeks. The L-AA supplement group with the lowest concentration (0.33 g/l L-AA) achieved mean plasma levels of 7 ± 1.38 μM, approximately one-eighth that of the normal level (mean plasma L-AA level in outbred Wistar rats was found to be 58 ± 3 μM) whilst those in the higher supplement group (3.33 g/l L-AA) achieved a mean of 18 ± 1.25 μM. All of the animals employed in the present study survived for 26 weeks and showed no clinical signs of L-AA deficiency during this period.

scholarly journals Mayer-Rokitansky-Küster-Hauser syndrome with 22q11.21 microduplication: a case report

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Domenico Dell’Edera ◽  
Arianna Allegretti ◽  
Mario Ventura ◽  
Ludovica Mercuri ◽  
Angela Mitidieri ◽  
...  
Keyword(s):  
Learning Difficulties ◽  
Clinical Signs ◽  
Mendelian Inheritance ◽  
Comparative Genomic ◽  
Chromosome 22 ◽  
Case Presentation ◽  
Mrkh Syndrome ◽  
Altered Gene Expression ◽  
Congenital Condition ◽  
Altered Gene

Abstract Background Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome (Online Mendelian Inheritance in Man [OMIM] #277000) is a congenital condition characterized by the total or partial agenesis of vagina and uterus. Agenesis can be isolated (MRKH 1) or associated with other renal, vertebral or cardiac defects (MRKH 2). Case presentation In this paper, we report a case of a Caucasian patient showing the clinical signs associated with MRKH. Array-based comparative genomic hybridization (a-CGH) analysis revealed a microduplication of approximately 3.01 megabases (Mb) located on the long arm of chromosome 22 (22q11.21). Microduplications affecting the 22q11.21 region have been shown to be associated with MRKH syndrome and Müllerian aplasia. The phenotype of patients with 22q11.2 duplication (OMIM #608363) appears extremely variable, ranging from apparently normal to mild learning difficulties or with multiple defects, sharing features with DiGeorge/velocardiofacial (DGS/VCFS) syndrome. Conclusions The altered gene expression together with other genetic, nongenetic, epigenetic or environmental factors can cause the extremely variable phenotype in patients carrying such duplication. Therefore, we can consider MRKH syndrome to be one of the clinical features of DGS/VCFS syndrome.

scholarly journals Transcriptomic Analysis Reveals Candidate Genes Responsive to Sclerotinia scleroterum and Cloning of the Ss-Inducible Chitinase Genes in Morus laevigata

2020 ◽  
Vol 21 (21) ◽  
pp. 8358
Author(s):  
Huanhuan Jiang ◽  
Xiaoyun Jin ◽  
Xiaofeng Shi ◽  
Yufei Xue ◽  
Jiayi Jiang ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Molecular Basis ◽  
Expression Patterns ◽  
Interaction Network ◽  
Sclerotinia Stem Rot ◽  
Response Characteristics ◽  
Kegg Pathways ◽  
Cdna Sequences ◽  
Chitinase Genes ◽  
Morus Laevigata

Sclerotinia sclerotiorum (Ss) is a devastating fungal pathogen that causes Sclerotinia stem rot in rapeseed (Brassica napus), and is also detrimental to mulberry and many other crops. A wild mulberry germplasm, Morus laevigata, showed high resistance to Ss, but the molecular basis for the resistance is largely unknown. Here, the transcriptome response characteristics of M. laevigata to Ss infection were revealed by RNA-seq. A total of 833 differentially expressed genes (DEGs) were detected after the Ss inoculation in the leaf of M. laevigata. After the GO terms and KEGG pathways enrichment analyses, 42 resistance-related genes were selected as core candidates from the upregulated DEGs. Their expression patterns were detected in the roots, stems, leaves, flowers, and fruits of M. laevigata. Most of them (30/42) were specifically or mainly expressed in flowers, which was consistent with the fact that Ss mainly infects plants through floral organs, and indicated that Ss-resistance genes could be induced by pathogen inoculation on ectopic organs. After the Ss inoculation, these candidate genes were also induced in the two susceptible varieties of mulberry, but the responses of most of them were much slower with lower extents. Based on the expression patterns and functional annotation of the 42 candidate genes, we cloned the full-length gDNA and cDNA sequences of the Ss-inducible chitinase gene set (MlChi family). Phylogenetic tree construction, protein interaction network prediction, and gene expression analysis revealed their special roles in response to Ss infection. In prokaryotic expression, their protein products were all in the form of an inclusion body. Our results will help in the understanding of the molecular basis of Ss-resistance in M. laevigata, and the isolated MlChi genes are candidates for the improvement in plant Ss-resistance via biotechnology.

A NEW METHOD OF DETERMINING THRESHOLD OF GENE NETWORK BASED ON PHENOTYPES

2011 ◽  
Vol 19 (04) ◽  
pp. 607-616
Author(s):  
YUANYUAN ZHANG ◽  
SHUDONG WANG ◽  
MEIXI YANG ◽  
DASHUN XU ◽  
DAZHI MENG
Keyword(s):  
Gene Networks ◽  
Gene Network ◽  
Structural Parameters ◽  
Network Modeling ◽  
Genetic Diseases ◽  
Disease Stage ◽  
External Representation ◽  
Functional Relationships ◽  
Disease Phenotypes ◽  
Significant Difference

With the rapid growth of microarray data, it has become a hot topic to reveal complex behaviors and functions of life system by studying the relationships among genes. In the process of reverse network modeling, the relationships with less relevance are generally not considered by determining a threshold when the relationships among genes are mined. However, there are no effective methods to determine the threshold up to now. It is worthwhile to note that the phenotypes of genetic diseases are generally regarded as external representation of the functions of genes. Therefore, two types of phenotype networks are constructed from gene and disease views, respectively, and through comparing these two types of phenotype networks, the threshold of gene network corresponding to a certain disease can be determined when their similarity reaches to maximum. Because the gene network is determined based on the relationships among phenotypes and phenotypes are external representation of the functions of genes, it is considered that relationships in the gene network may show functional relationships among genes in biological system. In this work, the thresholds 0.47 and 0.48 of gene network are determined based on Parkinson disease phenotypes. Furthermore, the validity of these thresholds is verified by the specificity and susceptibility of phenotype networks. Also, through comparing the structural parameters of gene networks for normal and disease stage at different thresholds, significant difference between the two gene networks at threshold 0.47 or 0.48 is found. The significant difference of structural parameters further verifies the efficiency of this method.

scholarly journals Pathology and Pathophysiology of Inhalational Anthrax in a Guinea Pig Model

2013 ◽  
Vol 81 (4) ◽  
pp. 1152-1163 ◽  
Author(s):  
Vladimir Savransky ◽  
Daniel C. Sanford ◽  
Emily Syar ◽  
Jamie L. Austin ◽  
Kevin P. Tordoff ◽  
...  
Keyword(s):  
Animal Model ◽  
Guinea Pig ◽  
Lymph Nodes ◽  
Guinea Pigs ◽  
Alternative Model ◽  
Lethal Dose ◽  
Clinical Signs ◽  
Regional Lymph Nodes ◽  
Content Type ◽  
Ames Strain

ABSTRACTNonhuman primates (NHPs) and rabbits are the animal models most commonly used to evaluate the efficacy of medical countermeasures against anthrax in support of licensure under the FDA's “Animal Rule.” However, a need for an alternative animal model may arise in certain cases. The development of such an alternative model requires a thorough understanding of the course and manifestation of experimental anthrax disease induced under controlled conditions in the proposed animal species. The guinea pig, which has been used extensively for anthrax pathogenesis studies and anthrax vaccine potency testing, is a good candidate for such an alternative model. This study was aimed at determining the median lethal dose (LD50) of theBacillus anthracisAmes strain in guinea pigs and investigating the natural history, pathophysiology, and pathology of inhalational anthrax in this animal model following nose-only aerosol exposure. The inhaled LD50of aerosolized Ames strain spores in guinea pigs was determined to be 5.0 × 104spores. Aerosol challenge of guinea pigs resulted in inhalational anthrax with death occurring between 46 and 71 h postchallenge. The first clinical signs appeared as early as 36 h postchallenge. Cardiovascular function declined starting at 20 h postexposure. Hematogenous dissemination of bacteria was observed microscopically in multiple organs and tissues as early as 24 h postchallenge. Other histopathologic findings typical of disseminated anthrax included suppurative (heterophilic) inflammation, edema, fibrin, necrosis, and/or hemorrhage in the spleen, lungs, and regional lymph nodes and lymphocyte depletion and/or lymphocytolysis in the spleen and lymph nodes. This study demonstrated that the course of inhalational anthrax disease and the resulting pathology in guinea pigs are similar to those seen in rabbits and NHPs, as well as in humans.

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